Human papillomavirus (HPV-16) is an important factor in the development of many tonsil and/or base of tongue squamous cell cancers. Although HPV-16 is not thought to cause cancer by itself, it appears to contribute to the development of tonsil and/or base of tongue cancer in many patients. It is likely that treatment for many patients with tonsil and/or base of tongue cancer could be improved if effective therapy to control HPV-16 is developed. The investigators in this study want to learn if ribavirin shows evidence of activity against HPV-16.

Ribavirin is a pill therapy that is approved by the Food and Drug Administration (FDA) as part of the standard treatment for Hepatitis C. Laboratory experiments suggest that ribavirin might also be useful in the treatment of head and neck cancers. However, ribavirin has not yet been tested against head and neck cancer in patients. The purpose of this study is to find out the effects of ribavirin on tonsil and base tongue squamous cell cancer in patients.

The main purpose of this study is to see if ribavirin changes the expression of certain proteins related to HPV infection in the tumor. The study will also find out if ribavirin changes how the tumor appears in a PET/CT scan (positron emission tomography/computed tomography scan).

Inclusion Criteria:

• Prior diagnostic surgical or core needle biopsy, with confirmation of tonsil and/or base of tongue squamous cell carcinoma that is positive for expression of p16 and phosphorylated eIF4E, as determined by the Department of Pathology at MSKCC. The biopsy may be either of the tonsil base of tongue and/or an involved neck node. 2 unstained slides and/or tissue block must be available from the initial diagnostic biopsy
• Positive expression p16 and phosphorylated eIF4E is defined as >=30% of tumor cells with cytological and/or nuclear staining
• Age ≥ 18 and ≤ 65 years of age
• Karnofsky Performance Status ≥ 80
• Adequate organ function, as follows:

Adequate bone marrow reserve: absolute neutrophil count (ANC) ≥ 1.5 X 109/L, platelets ≥ 160 X 109/L, hemoglobin ≥ 12 g/dL Hepatic: total bilirubin within 1.5 X upper limit of normal (ULN) ; alkaline phosphatase (AP), aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 X ULN (Patients with Gilbert's syndrome as the cause of hyperbilirubinemia may be eligible if total bilirubin ≤ 2.5 X UNL) Renal: Serum creatinine ≤ 1.3 mg/dL. Patients with serum creatinine > 1.3 mg/dL may be eligible if creatinine clearance (CrCl) ≥ 55 mL/min based on the standard Cockroft and Gault formula.

• Patients of childbearing potential must have a negative serum pregnancy test within 14 days of treatment. Patients must agree to use a reliable method of birth control during and for 6 months following the last dose of study drug.
• Ability to swallow oral medication.
• Non-surgical patients: If primary radiation +/- chemotherapy (concurrent or sequential) is planned, patients must agree to undergo research biopsy after completion of ribavirin treatment.

Exclusion Criteria:

• Prior chemotherapy or radiation for tonsillar or base of tongue squamous cell cancer
• More than 10 pack-years of tobacco use
• History of hemolytic anemia or thalassemia
• Active infection or serious underlying medical condition that would impair the patient's ability to receive protocol treatment.
• Current therapeutic anticoagulation with Coumadin (warfarin)
• Current or prior treatment with ribavirin
• Known active Hepatitis B or C
• Any prior documented history of transient ischemic attack (TIA) or cerebrovascular accident (CVA)
• New York Heart Association (NYHA) Grade II or greater congestive heart failure
• Clinically significant peripheral vascular disease
• History of unstable angina or myocardial infarction (MI) within the last 3 years

Up to 1 year